Inflammatory skin diseases encompass many pathologies such as rosacea, psoriasis, contact eczema, atopic dermatitis, or further pruritus.
Rosacea is a chronic and gradual common inflammatory dermatosis related to vascular disorders. It mainly affects the central portion of the face and is characterized by reddening of the face accompanied by hot flushes, facial erythema, papules, pustules, telangiectasia and sometimes ocular lesions called ocular rosacea. In extreme cases, particularly in humans, hypertrophy is observed at the nasal level called rhinophyma. Rosacea occurs between 25 and 70 years old and develops over several years with remission phases and exacerbation phases. Rosacea is much more common in persons with a pale complexion and particularly affects women. However, the most severe attacks are generally observed in men. Rosacea is classified in 4 sub-types depending on various clinical characteristics (Wilkin J et al., JAAD, 2002, 46: 584-587): erythematotelangiectatic rosacea (sub-type 1), papulopustular rosacea (sub-type 2), phymatous rosacea (sub-type 3) and ocular rosacea (sub-type 4). Rarer forms of rosacea also exist such as the granulomatous variant which is characterized by papules or yellow, brown or red indurated nodules, and by monomorphic lesions at the papules.
The pathological signs of rosacea vary according to the sub-type of the disease. Nevertheless, it is noted that local inflammatory reactions and vascular hyperactivity are constant signs of rosacea.
The pathogenesis of rosacea is poorly known and may involve several factors. The disease may be caused or promoted by the presence of follicular microorganisms such as bacteria and mites Demodex Folliculorum, an aberrant innate immune response, an abnormal vascular reactivity and hypersensitivity to environmental stimuli such as exposure to UVs, sudden changes in temperature, consumption of hot drinks, spiced dishes and alcohol, strong emotions (stress, embarrassment, anger . . . ).
The state of the art describes several markers useful for diagnosis of rosacea: these are for example certain interleukins (WO2013/00872), chemokine receptors or actual chemokines (WO2013/060865), the histamine receptor of type 2 (HRH-2) (FR2960152) or further a TRPV (Transient Receptor Potential Vanilloid) receptor, preferably TRPV1 (WO2012/084870).
Psoriasis is a chronic dermatosis, which evolves with eruptions or with fits, which affects about 2% of the population. Psoriasis is characterized by epidermal hyperproliferation (accelerated renewal of the epidermis) associated with keratinization disorders. Psoriasic lesions generally appear as erythemato-squamous plaques, often pruriginous plaques. Infiltration of leukocytes and moderate inflammation of the dermis and of the epidermis is generally observed at the lesions, which suggests that psoriasis would be a self-immune disease. Psoriasis frequently affects friction areas like knees, elbows and the lumbar region as well as the scalp, the hands and the feet. Several forms of psoriasis are distinguished (guttate psoriasis, pustular psoriasis, . . . ), plaque psoriasis (or vulgar psoriasis) being the most common form. Etiology of psoriasis at the present time remains poorly known. One case out of two seems to be of family origin. Various predisposition genes have been discovered (for example the allele gene HLA-Cw6). Recent studies suggest that psoriasis also results from immune anomalies (for example involvement of the (IL)-23/T-helper (Th)17 axis).
Eczema groups together pruriginous erythemato-vesicular inflammatory dermatoses. These pathologies generally develop in several phases: an erythematous phase, a vesicular phase, an exudation phase and a desquamation phase. Nummular eczema, contact eczema which is induced by an allergic reaction towards an exogenous agent, and atopic dermatitis are distinguished inter alia.
Atopic dermatitis (also called atopic dermitis or atopic eczema) is a chronic dermatosis, evolving with eruptions and which essentially affects children, in particular newly born children. Atopic dermatitis is characterized by significant skin dryness (xerosis), by papular or vesicular, squamous erythematous inflammatory lesions, with possibly cracks and lichenification of lesions. Atopic eczema affects the convexities of the cheeks, of the limbs and of the scalp in newly born children. In older children and in adults, the lesions are essentially located at the folds. Just like rosacea and psoriasis, pathogenesis of atopic dermatitis is poorly known. Genetic predisposition and/or an immune anomaly is often put forward (for example a filaggrin deficiency).
Finally, pruritus is a functional disorder which may be defined as “a sensation which causes the need to scratch oneself”. It may be localized or generalized. This is a frequent symptom, in particular of inflammatory dermatoses with skin lesions such as psoriasis and atopic dermatitis. Nevertheless, certain prurituses are not associated with specific skin lesions (pruritus “sine material”). The pruritus may then be caused by a general disease, be of neurological or psychological origin or be associated with skin dryness (xerosis). The pruritus may be caused or worsened by hypersensitivity to external factors (chemicals, temperature and humidity variations, hard water . . . ). In certain cases, the pruritus is a neurological sign sustained and/or amplified by a local inflammatory reaction resulting from the scratching. There is no general marker of pruritus.
At the present time there still exists a need for new biochemical tools and new methods for diagnosing inflammatory skin diseases, in particular rosacea.
The voltage-dependent sodium channels are essential actors of the initiation and of the propagation of action potentials at so-called “excitable” cells. These sodium channels are mainly expressed at the neurones of the central and peripheral nervous system and at muscle cells. These are transmembrane proteins comprising a wide alpha (α) sub-unit of about 260 kDa associated with one or several beta sub-units from 33 to 38 kDa. The alpha sub-unit forms the core of the channel and comprises four homologous membrane domains (I-IV), each consisting of 6 transmembrane segments (S1-S6). The membrane domains of the alpha sub-unit are connected with each other through large intracellular loops which comprise many regulation sites. The alpha sub-unit is responsible for conductance and selectivity properties of the channel while the beta sub-units are involved in the stabilization and in the kinetic properties of the channel. To this day, 10 isoforms for the alpha sub-unit have been identified in humans. The name assigned to these isoforms contains the symbol of the transported ion (Na), with as an index the regulating element (voltage v). The figures which follow, designate the sub-family of genes and the number associated with the relevant isoform. To this day, the main sub-family of genes identified comprises the isoforms Nav 1.1 to Nav 1.9. An additional isoform, further away, Nax has also been identified. The percentage of sequence identity between the different isoforms Nav 1.1 to Nav 1.9 is of at least 60%. The isoforms Nav 1.1 to Nav 1.9 inter alia differ by their sensitivity to tetrodotoxin (TTX), a very powerful and selective blocker of sodium channels, and by their tissue distribution. The isoforms Nav 1.1 to Nav 1.4, Nav 1.6 and Nav 1.7 are said to be sensitive to TTX with EC50 s of the order of one nanomolar. The isoforms Nav 1.5, Nav 1.8 and Nav 1.9 as for them are considered as resistant to TTX with EC50 s of the order of one micromolar (μM). In this respect, the EC50 of TTX for Nav 1.9 is of about 200 μM. As regards the tissue distribution, the isoforms Nav 1.1, Nav 1.2, Nav 1.3 and Nav 1.6 are mainly expressed at the central nervous system. The isoform Nav 1.4 is mainly expressed at skeletal myocytes while Nav 1.5 is essentially present, in adults, at the cardiomyocytes. Finally, the isoforms Nav 1.7, Nav 1.8 and Nav 1.9 are expressed at the peripheral nervous system (PNS). Nav 1.9 was mainly detected at the sensitive neurones of spinal ganglia by immuno-marking experiments and by PCR. Nav 1.9 would play a role in perception of pain (nociception). Finally, Nax is expressed at the heart, the uterus, smooth muscles, astrocytes and certain neurones of the hypothalamus and of the central nervous system. For a review relating to the voltage-dependent sodium channels, reference may be made to Yu and Caterall, Genome Biology, 2003, 4:207 or Caterall et al., Pharmacological Reviews, 2005, 57:397-409.
To the knowledge of the Applicants, no link was established in the state of the art between the expression of an isoform of Nav, in particular Nav 1.9, and inflammatory skin diseases.